To elicit its characteristic biological response in the body, a drug must be available in an effective concentration at its site of action. The concentration of a drug that reaches its reactive site varies with such factors as the amount of drug administered, the extent and rate of its absorption, distribution, binding or localization in tissues, its biotransformation, and its excretion. (For a review of these topics, see Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 6th edition, MacMillan Publishing Co., Inc., New York, 1980, pp. 1-39.) The foregoing factors, and hence the ultimate efficacy of a particular drug, are in turn influenced by the route chosen for drug administration.
The common routes of drug administration are enteral (oral ingestion) and parenteral (intravenous, subcutaneous, and intramuscular) routes of administration. To determine the appropriate mode of drug administration, it is necessary to understand some of the advantages and disadvantages of the route used. For example, intravenous drug administration is advantageous for emergency use when very rapid increases in blood levels are necessary. The intravenous route allows for dosage adjustments when required, and is also useful for administration of large volumes of a drug when diluted. However, there are limitations on the usefulness of intravenous drug administration. One problem is the risk of adverse effects resulting from the rapid accumulation of high concentrations of the drug in plasma and tissues. Consequently, intravenously administered drug solutions must generally be continuously monitored and injected slowly. The intravenous route is not suitable for oily or insoluble substances. Furthermore, intravenous administration is restricted to trained medical personnel.
Other routes of parental administration are often inconvenient or painful for patients especially if frequent administration is required. Subcutaneous injection is used for drugs that are not irritating. This mode of administration is not suitable for delivering large volumes nor is it suitable for administering irritating substances which may cause pain or necrosis at the site of injection. Intramuscular administration is generally suitable for moderate volumes, oily substances, and some irritating substances. The intramuscular route cannot be used during anticoagulant medication and may interfere with the interpretation of certain diagnostic tests.
Oral administration of drugs is generally more convenient and economical and is most acceptable to humans. However, this route of administration requires patient cooperation. Absorption may be inefficient (i.e., incomplete) for poorly soluble, slowly absorbed, or unstable drug preparations, and the time from ingestion to absoption may prohibit effective use in emergency situations. Furthermore, peptides and proteins will often be destroyed by the digestive enzymes, acid, and surface-active lipids in the gut prior to reaching the site of action.
Certain drugs which need to be administered frequently are not effectively absorbed when administered orally and hence must be delivered by injection methods. Yet, a number of problems are associated with conventional injection therapies.
By way of illustration, conventional insulin therapy requires frequent insulin injections resulting in discomfort and disruption of the patient's lifestyle. Hence, many diabetics either refuse insulin therapy altogether or avoid intensive treament regimens such as those which involve injections with each meal. In addition, certain patients, especially young children, elderly patients, and those who are blind and/or disabled, often have difficulty with insulin self-administration by injection. Furthermore, insulin absorption after subcutaneous injection is variable in terms of rate and amount depending upon factors such as exercise, local blood flow, depth and volume of injection, the presence of local proteases which degrade insulin, and perhaps other, unknown factors. Even presently available short acting and long acting preparations of insulin or mixtures thereof cannot mimic the daily glucose and insulin excursions of non-diabetic individuals. Portable infusion pumps have now been employed to increase the ease of delivering subcutaneously meal-related insulin boluses. However, these devices are externally worn and are therefore cumbersome. They require regular needle replacement, are complicated by local infections at the site of needle placement, are expensive, and are not acceptable to many patients.
It is clear that a reproducible, reliable, and non-invasive means for delivering drugs such as insulin would be highly desirable. What is needed especially in the case of insulin is a delivery system that would permit easy, rapid, and non-invasive administration of insulin at meal times when blood glucose concentration rises to peak levels. Since the discovery of insulin six decades ago, there have been many attempts to develop alternate means of insulin delivery. For instance, insulin has been administered enterally, either alone or encapsulated in liposomes (microcapsules), sublingually, vaginally, and rectally, with and without surfactants.
In addition to the preceding routes of administration, the nasal route has been the subject of investigation for the delivery not only of insulin but of other drugs as well. It is known that certain very small peptides can be absorbed through the nasal mucosa as a "snuff" or directly from aqueous solution without an adjuvant. Examples of peptides which can sometimes be administered by this route are adrenocorticotrophic hormone (ACTH), luteinizing hormone releasing hormone (LHRH), oxytocin and vasopressin. Indeed, for patients with diabetes insipidus, the intranasal route is frequently the means for vasopressin delivery.
In contrast to these directly administrable compounds, many drugs such as insulin are inefficiently absorbed across mucous membranes at physiological pH in the absence of adjuvants. Several workers have attempted to mix insulin with adjuvants that might enhance nasal insulin absorption. Hirai et al., Int. J. Pharmaceutics (1981) 9: 165-184; Hirai et al., Diabetes (1978) 27: 296-299; British Pat. No. 1,527,605; and U.S. Pat. No. 4,153,689; and Pontiroli et al. (1982) Br. Med. J. 284: 303-386, have described the use of various bile salts to enhance absorption of insulin by the nasal mucosa.
While the nasal mucosal route has received considerable attention for systemic drug delivery, it has also hitherto been known that drugs may be applied to mucous membranes of the conjunctiva, nasopharynx, oropharynx, ear canal, respiratory tract, vagina, rectum, colon, and urinary bladder for their local effects.